1. Field of the Invention
The present invention is a process and intermediates to produce a pharmaceutically useful compound, (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (VII).
2. Description of the Related Art
U.S. Pat. No. 5,273,975 discloses a genus which includes (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one. (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (VII) can be made by the process disclosed in U.S. Pat. No. 5,273,975.
U.S. Pat. No. 5,652,245 discloses a process to produce heterocyclic amines similar to those of U.S. Pat. No. 5,273,975. In addition, it discloses a process which can be used to make (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (VII).
Disclosed is a tricyclic compound of formula (II) where RN is selected from the group consisting of:
(A) xcfx86-CH2xe2x80x94 where phenyl is optionally substituted with 1 or 2: (1) C1-C4 alkoxy, (2) Fxe2x80x94, (3) Clxe2x80x94, (4) Brxe2x80x94, (5) Ixe2x80x94, (6) C1-C4 alkyl,
(B) RN1xe2x80x94H2xe2x80x94Oxe2x80x94CH2xe2x80x94 where RN1 is selected from the group consisting of:
(1) xcfx86- optionally substituted with: (a) C1-C4 alkyl, (b) Fxe2x80x94, (c) Clxe2x80x94, (d) Brxe2x80x94, (e) Ixe2x80x94, (f) C1-C4 alkoxy,
(2) (CH3)3Sixe2x80x94CH2xe2x80x94,
(3) RN2xe2x80x94Oxe2x80x94CH2xe2x80x94 where RN2 is C1-C4 alkyl,
(4) CH2xe2x95x90CHxe2x80x94,
(5) xe2x80x94H,
(6) C1-C4 alkyl;
(C) an unsaturated compound selected from the group consisting of: (1) CH2xe2x95x90CHxe2x80x94CH2xe2x80x94, (2) CH3xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94 and (3) xcfx86-CHxe2x95x90CHxe2x80x94CH2xe2x80x94.
Also disclosed is a hydroxy compound of formula (III) where RN is as defined above and where RX is selected from the group consisting of xe2x80x94Br, xe2x80x94Cl and xe2x80x94I.
Further, disclosed is an ester of formula (IV) where RN is as defined above.
Additionally disclosed is the hydroxy-amino compound of formula (V) where RN is as defined above.
Disclosed is the tetracyclic compound of formula (VI) where RN is as defined above.
(5R)-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (VII) is known to be useful a pharmaceutical agent, see U.S. Pat. No. 5,273,975. Because the compound has an enantiomeric center it is difficult to prepare this compound optically pure. One can produce the compound in racemic form and then resolve it by known means.
The invention here is a stereoselective synthetic process to preapre (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (VII) which produces the desired enantiomer utilizing resolution of diastereomers. The material which is lost, is recycled back to the starting material (I).
The process of the present invention is the same regardless of which of the variable substituents RN and RX are utilized with the exception of how the RN protective group is removed. This is well known to those skilled in the art.
The starting material, 1,2-dihydro-4H-imidazo[5,4-1-ij]quinolin-2-one (I) is known, see J. Heterocyclic Chem., 19, 837-49 (1982). The unsubstituted tricyclic amide (I) is transformed to the corresponding tricyclic amide (II) by means well known to those skilled in the art for transformation of an amide to a substituted amide. The tricylic amide (II) requires the amide nitrogen atom be protected by RN. Operable RN groups include:
(A) xcfx86-CH2xe2x80x94 where phenyl is optionally substituted with 1 or 2:
(1) C1-C4 alkoxy, (2) Fxe2x80x94, (3) Clxe2x80x94, (4) Brxe2x80x94, (5) Ixe2x80x94, (6) C1-C4 alkyl,
(B) RN1xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 where RN1 is selected from the group consisting of:
(1) xcfx86 optionally substituted with:
(a) C1-C4 alkyl, (b) Fxe2x80x94, (c) Clxe2x80x94, (d) Brxe2x80x94, (e) Ixe2x80x94, (f) C1-C4 alkoxy,
(2) (CH3)3Sixe2x80x94CH2xe2x80x94,
(3) RN2xe2x80x94Oxe2x80x94CH2xe2x80x94 where RN2 is C1-C4 alkyl,
(4) CH2xe2x95x90CHxe2x80x94
(5) xe2x80x94H,
(6) C1-C4 alkyl;
(C) an unsaturated compound selected from the group consisting of:
(1) CH2xe2x95x90CHxe2x80x94CH2xe2x80x94, (2) CH3xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94 and (3) xcfx86-CHxe2x95x90CHxe2x80x94CH2xe2x80x94. It is preferred that RN be xcfx86-CH2xe2x80x94.
When the RN protecting group is xcfx86-CH2xe2x80x94 optionally substituted with (A) xcfx86-CH2xe2x80x94 where phenyl is optionally substituted with 1 or 2 C1-C4 alkoxy, Fxe2x80x94, Clxe2x80x94, Brxe2x80x94, Ixe2x80x94 and C1-C4 alkyl, this protecting group is removed by use of metal/ammonia at the same time the aziridine (VI) is opened. When the RN protecting group is non-benzyl, such as (CH3)3Sixe2x80x94CH2xe2x80x94 this group is removed with fluoride ion or strong acid. When the RN protecting group is non-benzyl, non-silyl, such as RN2xe2x80x94Oxe2x80x94CH2xe2x80x94 where RN2 is C1-C4 alkyl this group is removed by Lewis acid such as zinc chloride or Bronsted acid. When the RN protecting group is an unsaturated non-benzyl, such as CH2xe2x95x90CHxe2x80x94 this group is removed by palladium catalysis in the presence of a nucleophile. All of these removal methods are well known to those skilled in the art, see for example, Protective Groups In Organic Synthesis, Wiley and Sons, 1991.
The tricyclic amide (II) is transformed to the corresponding hydroxy compound (III) by reaction with an agent which can produce a halohydrin (III). Suitable agents include dibromantin (or its equivalent with other than bromine when RX is other than xe2x80x94Br). Operable RX include xe2x80x94Cl, xe2x80x94Br and xe2x80x94I; it is preferred that RX be xe2x80x94Br. It is preferred to use an aprotic solvent such as acetonitrile, a catalytic amount of fluoboric acid at a low temperature of about 0xc2x0; see EXAMPLE 2.
The optically impure hydroxy compound (III) is reacted with the acid chloride, naproxen chloride (PREPARATION I), to form diastereoisomeric esters (IVA) and (IVB); see EXAMPLE 3. The isomer that will produce the desired product (VII), is ester (IVA). The ester (IVB) is useful because it can be readily transformed back to the tricyclic compound (II), by known means, and be recycled.
The ester (IVA) is then converted to the corresponding hydroxy-amino compound (V) by the process of EXAMPLE 4.
The hydroxy-amino compound (V) is transformed to the corresponding tetracyclic compound (VI) by a multi-step reaction. First the hydroxy-amino compound (V) is contacted with a strong base. Preferred strong bases are alkyl lithium reagents (such as butyllithium, methyllithium), potassium hexamethyldisilazide and lithium diisopropylamide. Following the contacting with a strong base, the reaction mixture of step (1) is contacted with a compound of the formula RSxe2x80x94SO2xe2x80x94X where RS is phenyl and substituted phenyl and where X is xe2x80x94Cl or xe2x80x94Br. It is preferred that RS is phenyl or tolyl. The final step is quenching with a weak base. Suitable weak bases include bicarbonate, carbonate, (phosphate) buffers and hydroxide; preferred is bicarbonate. The preferred process is exemplified in EXAMPLE 5.
The tetracyclic compound (VI) is transformed to the corresponding methylamine (VII) by the process of EXAMPLE 6. The nature of this cleavage reaction depends on the particular RN attached to the tetracyclic compound (VI). This reaction is either a metal ammonia reduction or a metal catalyzed hydrogenolysis. This process opens the aziridine ring.
The methylamine (VII) is transformed to the desired (maleic) salt by the process of EXAMPLE 7.
The methylamine (VII), and its pharmaceutically acceptable salts, are known to be useful as a pharmaceutical agent in treating those individulas who have Parkinson""s Disease, see U.S. Pat. No. 5,273,975.
It is preferred that the maleic salt (VIII) be administered in the pharmaceutical dosage form describe in U.S. Pat. No. 6,197,339.
The exact dosage and frequency of administration depends on the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the methylamine (VI) and its metabolites in the patients blood and/or the patient""s response.
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol xe2x80x9cxe2x80x94xe2x80x9d in general represents a bond between two atoms in the chain. Thus CH3xe2x80x94Oxe2x80x94CH2xe2x80x94CH(Ri)xe2x80x94CH3 represents a 2-substituted-1-methoxypropane compound. In a similar fashion, the symbol xe2x80x9cxe2x95x90xe2x80x9d represents a double bond, e.g., CH2xe2x95x90C(Ri)xe2x80x94Oxe2x80x94CH3, and the symbol xe2x80x9cxc2x0xe2x80x9d represents a triple bond, e.g., HCxc2x0Cxe2x80x94CH(Ri)xe2x80x94CH2xe2x80x94CH3. Carbonyl groups are represented in either one of two ways: xe2x80x94COxe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94, with the former being preferred for simplicity.
When a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable. For example, a variable Ri attached to a carbon atom as xe2x80x94C(xe2x95x90Ri)xe2x80x94 might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (xe2x80x94COxe2x80x94) or as two separately attached monovalent variable substituents Ixe2x80x94Ri-j and xcex2xe2x80x94Ri-k. When a bivalent variable, Ri, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form xe2x80x9cIxe2x80x94Ri-j:xcex2xe2x80x94Ri-kxe2x80x9d or some variant thereof. In such a case both Ixe2x80x94Ri-j and xcex2xe2x80x94Ri-k are attached to the carbon atom to give xe2x80x94C(Ixe2x80x94Ri-j)(xcex2xe2x80x94Ri-k)xe2x80x94. For example, when the bivalent variable R6, xe2x80x94C(xe2x95x90R6)xe2x80x94 is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are Ixe2x80x94R6-1:xcex2xe2x80x94R6-2, . . . Ixe2x80x94R6-9:xcex2xe2x80x94R6-10, etc., giving xe2x80x94C(Ixe2x80x94R6-1)(xcex2xe2x80x94R6-2)xe2x80x94, . . . xe2x80x94C(Ixe2x80x94R6-9)(xcex2xe2x80x94R6-10)xe2x80x94, etc. Likewise, for the bivalent variable R11, xe2x80x94C(xe2x95x90R11)xe2x80x94, two monovalent variable substituents are Ixe2x80x94R11-1:xcex2xe2x80x94R11-2. For a ring substituent for which separate I and xcex2 orientations do not exist (e.g. due to the presence of a carbon carbon double bond in the ring), and for a substituent bonded to a carbon atom which is not part of a ring the above convention is still used, but the I and xcex2 designations are omitted.
Just as a bivalent variable may be defined as two separate monovalent variable substituents, two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example, in the formula xe2x80x94C1(Ri)Hxe2x80x94C2(Rj)Hxe2x80x94 (C1 and C2 define arbitrarily a first and second carbon atom, respectively) Ri and Rj may be defined to be taken together to form (1) a second bond between C1 and C2 or (2) a bivalent group such as oxa (xe2x80x94Oxe2x80x94) and the formula thereby describes an epoxide. When Ri and Rj are taken together to form a more complex entity, such as the group xe2x80x94Xxe2x80x94Yxe2x80x94, then the orientation of the entity is such that C1 in the above formula is bonded to X and C2 is bonded to Y. Thus, by convention the designation xe2x80x9c. . . Ri and Rj are taken together to form xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94 . . . xe2x80x9d means a lactone in which the carbonyl is bonded to C2. However, when designated xe2x80x9c. . . Rj and Ri are taken together to form xe2x80x94COxe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 the convention means a lactone in which the carbonyl is bonded to C1.
The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as xe2x80x9cC1-C4xe2x80x9d, where both xe2x80x9c1xe2x80x9d and xe2x80x9c4xe2x80x9d are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, xe2x80x9cC1-C4 alkylxe2x80x9d represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C2-C4 alkoxycarbonyl describes a group CH3xe2x80x94(CH2)nxe2x80x94Oxe2x80x94COxe2x80x94 where n is zero, one or two. By the second method the carbon atom content of only each portion of the definition is indicated separately by enclosing the xe2x80x9cCi-Cjxe2x80x9d designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C1-C3)alkoxycarbonyl has the same meaning as C2-C4 alkoxy-carbonyl because the xe2x80x9cC1-C3xe2x80x9d refers only to the carbon atom content of the alkoxy group. Similarly while both C2-C6 alkoxyalkyl and (C1-C3)alkoxy(C1-C3)alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
The compounds of formulas (I) thru (VIII) are a rigid cyclic (ring) structure and therefore defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the rigid cyclic compound. Where the compounds have two substituents attached to a carbon atom, xe2x80x94C(X1)(X2)xe2x80x94, the two substituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial. However, the position of the two substituents relative to the ring and each other remains fixed. While either substituent at times may lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other relative to the viewer. In the chemical structural formulas (I) thru (VIII) of the invention depicting such compounds, a substituent (X1) which is xe2x80x9cbelowxe2x80x9d another substituent (X2) will be identified as being in the alpha (xcex1) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol xe2x80x9cxe2x80x94xe2x80x94xe2x80x94xe2x80x9d or being in the beta (xcex2) configuration and is indicated by an unbroken or solid line attachment to the carbon atom.
All temperatures are in degrees Centigrade.
TLC refers to thin-layer chromatography.
HPLC refers to high pressure liquid chromatography.
Saline refers to an aqueous saturated sodium chloride solution.
Chromatography (column and flash chromatography) refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
xcfx86- refers to phenyl (C6H5).
Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).